Abstract
Chronic kidney disease (CKD) is an inherently systemic disease that refers to a long-term loss of kidney function. The progression of CKD has repercussions for other organs, leading to many kinds of extrarenal complications. Intensive studies are now being undertaken to reveal the risk factors and pathophysiological mechanism of this disease. During the past 20 years, increasing evidence from clinical and basic studies has indicated that klotho, which was initially known as an anti-aging gene and is mainly expressed in the kidney, is significantly correlated with the development and progression of CKD and its complications. Here, we discuss in detail the role and pathophysiological implications of klotho in ion disorders, the inflammation response, vascular calcification, mineral bone disorders, and renal fibrosis in CKD. Based on the pathogenic mechanism of klotho deficiency and klotho decline in urine early in CKD stage 2 and even earlier in CKD stage 1, it is not difficult to understand that soluble klotho can serve as an early and sensitive marker of CKD. Moreover, the prevention of klotho decline by several mechanisms can attenuate renal injuries, retard CKD progression, ameliorate extrarenal complications, and improve renal function. In this review, we focus on the functions and pathophysiological implications of klotho in CKD and its extrarenal complications as well as its potential applications as a diagnostic and/or prognostic biomarker for CKD and as a novel treatment strategy to improve and decrease the burden of comorbidity in CKD.
Highlights
The klotho family and structure Klotho family members include α, β, and γ-klotho genes based on their predicted primary sequences [18, 19]. β- and γ-klotho were discovered based on their homology with α-klotho, and they all share a single-pass transmembrane protein [20, 21]. β-Klotho is predominantly expressed in the liver but is found in the kidney, gut, and spleen and mediates the activity of members of the fibroblast growth factor (FGF) family, such as FGF-19 and -21 [18, 22]. γ-Klotho is expressed in the kidney and skin and has undefined functions [18, 21]
Soluble klotho directly regulates phosphorus excretion in the kidney and participates in systemic mineral homeostasis by regulating 1α-hydroxylase activity and parathyroid hormone (PTH) and FGF23 secretion [49, 50]. These results suggest that klotho deficiency limits its regulation of FGF23 production and hyperphosphataemia remains the principal regulator of FGF23 secretion in Chronic kidney disease (CKD) [51]
Recent studies have confirmed that the stable delivery of soluble klotho can reduce chronic hyperphosphataemia and Vascular calcification (VC) in vitro and in vivo [99], and activating peroxisome proliferator-activated receptor γ enhanced the expression of klotho to inhibit Phosphate-induced VC in vascular smooth muscle cells (SMCs) [100]
Summary
Chronic kidney disease (CKD) is a progressive systemic disease that irreversibly alters the function and structure of the kidney, over months or years. CKD progression has repercussions for other organs, exerting multiple negative systemic effects on numerous organs, including those of the cardiovascular system, leading to cardiovascular diseases, which increase the risk of mortality [1]. In the past 3 decades, Intensive studies in animals and humans have been performed to reveal the risk factors and pathophysiological mechanism of this disease. These studies have established that the original disease process causes an initial loss of nephron unit; renal diseases progress to renal failure as a consequence of functional adaptations intervening in the kidney, leading to injury in other organs. Based on the relationship between klotho and CKD, we here systematically review the functions, physiopathological characteristics, and potential applications of klotho in the related signs and complications of CKD
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
